Platelet FcγRIIA-induced serotonin release exacerbates the severity of Transfusion-Related Acute Lung Injury in mice.
Fiche publication
Date publication
septembre 2021
Journal
Blood advances
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GACHET Christian
Tous les auteurs :
El Mdawar MB, Maître B, Magnenat S, Tupin F, Jonsson F, Gachet C, de la Salle H, Hechler B
Lien Pubmed
Résumé
Transfusion-related acute lung injury (TRALI) remains a major cause of transfusion-related fatalities. The mechanism of human antibody-mediated TRALI, especially the involvement of the Fcγ receptors, is not clearly established. Contrary to mice, human platelets are unique in their expression of the FcγRIIA/CD32A receptor, suggesting that our understanding of the pathogenesis of antibody-mediated TRALI is partial, since the current murine models incompletely recapitulate the human immunology. We evaluated the role of FcγRIIA/CD32A in TRALI using a humanized mouse model expressing the FcγRIIA/CD32A receptor. When challenged with a recombinant chimeric human IgG1/mouse anti-MHC I monoclonal antibody, these mice showed exacerbated alveolar edema and higher mortality compared to WT mice. Unlike in WT mice, monocytes/macrophages were accessory for TRALI initiation in CD32A+ mice pointing to the decisive contribution of another cell type. Platelet activation was dramatically increased in CD32A+ animals resulting in their increased consumption and massive release of their granule contents. Platelet depletion prevented the exacerbation of TRALI in CD32A+ mice but did not affect TRALI in WT animals. By blocking platelet serotonin uptake with fluoxetine, we showed that the severity of TRALI in CD32A+ mice resulted from the serotonin released by activated platelets. Furthermore, inhibition of 5-hydroxytryptamine 2A serotonin receptor with sarpogrelate, before or after the induction of TRALI, abolished the aggravation of lung edema in CD32A+ mice. Our findings demonstrate that platelet FcγRIIA/CD32A activation exacerbates antibody-mediated TRALI and provide a rationale for designing prophylactic and therapeutic strategies targeting the serotonin pathway to attenuate TRALI in patients.
Référence
Blood Adv. 2021 Sep 14;: